Leigh syndrome queries

[ValWood]

Hi,

I used to have quite a number of pombe genes annotated to Leigh syndrome and now we have only 2.

I was annotating SURF1 pombe ortholog and the paper states

This no longer has a Leigh syndrome connection.

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/surf1#:~:text=SURF1%20represents%20a%20major%20gene,and%20COX10%20which%20causes%20leukodystrophy.

states
SURF1 is the gene responsible for most of the COX-deficient cases of LS.

However I can only see these obsoletions on the tracker which does not seem to account for the decrease:
(presumably these were remapped to Leigh syndrome?)

From reading around, there are quite a number of causal genes (summarized thus by GPC chat)

SURF1: The most common nuclear gene associated with Leigh syndrome. Mutations in SURF1 affect complex IV (cytochrome c oxidase) of the mitochondrial respiratory chain.
PDHA1: This gene encodes the E1 alpha subunit of the pyruvate dehydrogenase complex, crucial for linking glycolysis to the TCA cycle.
NDUFS1, NDUFS4, NDUFA10: These genes are part of Complex I (NADH
oxidoreductase) of the mitochondrial respiratory chain.
SDHA, SDHB, SDHC, SDHD: These genes are components of Complex II (succinate dehydrogenase), which is also involved in the respiratory chain.
COX10, COX15: Mutations in these genes affect Complex IV (cytochrome c oxidase) function.
ATP5A1, ATP6, ATP8: These genes are involved in Complex V (ATP synthase), which is responsible for ATP production.
SLC19A3: This gene encodes a thiamine transporter, and mutations here can lead to a thiamine-responsive form of Leigh syndrome.

Mitochondrial DNA (mtDNA) mutations:
MT-ND genes (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6): These genes encode subunits of Complex I of the mitochondrial respiratory chain.
MT-ATP6: This gene is involved in the function of Complex V (ATP synthase).
MT-TL1 (mitochondrial tRNA leucine): Mutations in this gene can affect mitochondrial protein synthesis.
MT-CO genes (MT-CO1, MT-CO2, MT-CO3): These encode subunits of Complex IV (cytochrome c oxidase).

I do see some annotation in Monarch, but these are listed as "associated" rather than "causal"

https://medlineplus.gov/genetics/condition/leigh-syndrome/#causes
says that over 110 genes (it seems most OXPHOS genes can cause Leigh syndrome?)

(I'm not sure if this is a Monarch issue, a Mondo issue or both)

[twhetzel]

Hi @ValWood - thanks for posting this issue. For Mondo, gene associations are included when there is a single gene that is found to be the cause of the disease. In Monarch however, it includes genes that are both causal and associated with a disease. Most disease defining gene associations in Mondo currently come from OMIM. When I look at the OMIM page for SURF1 it lists two diseases. For 'Mitochondrial complex IV deficiency, nuclear type 1' it's currently a synonym on MONDO:0009068 'cytochrome-c oxidase deficiency disease', although this term is scheduled to be merged with MONDO:0033885 'mitochondrial complex IV deficiency, nuclear-type' (and it should have the SURF1 gene association added).

Searching OMIM for 'leigh syndrome', of the entries I see (OMIM:220111, OMIM:500017, or OMIM:256000) I do not see any with a Phenotype to Gene association with SURF1.

[cmungall]

@twhetzel is correct in that we currently take OMIM as an authority.

But I think this is a good example of where we could draw from other sources, particularly mitochondrial diseases; e.g the ClinGen mitochondrial disease expert panel regards SURF1<->Leigh as "definitive"
https://search.clinicalgenome.org/kb/genes/HGNC:11474

Biologically, SURF1 is an assembly factor for complex IV so it's likely to present similarly. I think we need to refactor the mitochondrial complex diseases. Some of this is in progress, see #7438